The Post-Exposure Prophylaxis of Infant (PEPI)-Malawi Study Sponsored by NICHD and CDC

Questions and Answers

1. What is the Post-Exposure Prophylaxis of Infant (PEPI)-Malawi Study and why was it conducted?

The PEPI-Malawi study is a Phase III clinical study conducted in Malawi that was funded by the National Institute of Child Health and Human Development and the Centers for Disease Control and Prevention. (Phase III clinical studies, or trials, test a promising new treatment by comparing it to a standard treatment. The PEPI trial was conducted in an attempt to prevent HIV transmission to infants who do not have HIV at birth, but are born to women who are HIV-infected. The study sought to determine if giving breastfeeding infants a regimen of nevirapine (NVP) for the first 14 weeks of life or NVP plus zidovudine (ZDV) for the first 14 weeks of life reduces the risk of HIV transmission through breastfeeding more than the current standard of care in Malawi. The current standard of care in Malawi involves giving a single dose of NVP to the mother during labor and to the infant at birth with daily ZDV given to the infant for the first week of life.

2. Where was the PEPI-Malawi study conducted and by whom?

The study was conducted at the Queen Elizabeth Central Hospital and 5 associated health centers in Blantyre, Malawi. The study was led by Newton I. Kumwenda, Ph.D. from the University of Malawi College of Medicine, Blantytre Malawi, and Taha E. Taha, M.D., Ph.D. from the Bloomberg School of Public Health at Johns Hopkins University in Baltimore, MD.

3. How was the study designed?

In the study, the current Malawi standard of care for prevention of mother-to-child HIV transmission was offered to all women who were screened and identified as HIV-infected. Women could be screened for HIV during labor or immediately after giving birth. All of the women were counseled about the risks of HIV transmission associated with breastfeeding. The infants of the mothers who chose to breastfeed and gave informed consent to participate were selected at random to receive either:

Single dose NVP plus 1 week of ZDV or

Single dose NVP plus 1 week of ZDV, with daily NVP starting at day 8 through 14 weeks of life (extended NVP) or

Single dose NVP plus 1 week of ZDV, with daily NVP plus ZDV starting at day 8 through 14 weeks of life (extended NVP+ZDV)

Only the infants who were HIV-uninfected at birth were included in the analysis of the study.

4. Why did the extended course of NVP or NVP+ZDV begin at day 8 rather than immediately?

All infants in this study received NVP at birth in keeping with the standard of care in Malawi. Because the drug generally remains in infants’ bodies for at least 7 days before their systems begin to clear it, researchers began giving the babies the extended daily NVP or NVP+ZDV regimens on their eighth day of life.

5. Why was 14 weeks chosen for the duration of the extended regimen?

The choice of providing the extended regimen for 14 weeks was based on the duration of the schedule for immunizing infants in Malawi, which is completed by 14 weeks. After the 14 week visit, infants do not return to the clinic until 9 months to receive measles immunization. For this reason, integrating the infant extended regimen with the immunization visits would allow improved follow-up and monitoring of safety for infants and potentially assist in implementing the prevention regimen in resource-limited settings if it proved successful.

6. What are the primary results of the study?

Both the extended NVP and extended NVP+ZDV regimens were found to be as safe as and more effective than the standard of care (single-dose NVP plus 1 week of ZDV) in reducing the rates of HIV transmission and improving HIV-free survival in breastfeeding infants born to HIV-infected women.

At 14 weeks of age, the risk of HIV transmission was 67 percent lower for infants who received the extended NVP regimen and 65 percent lower for infants who received the extended NVP+ZDV regimen compared with those who received the standard of care regimen.

At 9 months of age, the risk of HIV transmission was 51 percent lower for infants who received the extended NVP regimen and 39 percent lower for infants who received the extended NVP+ZDV regimen compared with those who received the standard of care regimen.

The risk of death was non-significantly lower in infants who received either of the extended regimens: at 9 months of age, the risk of death was 6.8 percent for infants who received the extended NVP regimen and 6.3 percent for infants who received the extended NVP+ZDV regimen compared to 8.9 percent for those who received the standard of care regimen. The primary causes of infant death were gastroenteritis and pneumonia.

The risk of HIV transmission or death (the correlate of HIV-free survival) in infants who received the extended NVP and extended NVP+ZDV regimens was significantly reduced at 14 weeks and 9 months compared with those who received the current standard of care.

7. Were there any differences between the extended NVP and extended NVP+ZDV treatments?

There were no statistically significant differences in HIV infection, death or HIV-free survival in infants who received the extended NVP regimen compared to those who received the two-drug NVP+ ZDV regimen.

8. When was the study conducted?

The study began in April 2004. The evaluation by the researchers includes all infants enrolled through August 7, 2007.

9. How many mother-infant pairs were included in the study?

As of August 7, 2007, the study had enrolled 3,016 infants who were uninfected at birth and had sufficient data for evaluation; 1,033 of these infants received the standard of care single dose NVP plus 1 week of ZDV regimen, 1,016 received the extended NVP regimen, and 997 received the extended NVP+ZDV regimen.

10. What drug or regimen is currently used to prevent mother-to-infant transmission of HIV?

Based on the 1999 results of the HIVNET 012 conducted in Uganda, one of the current standards of care used to reduce mother-to-child transmission of HIV in resource-limited settings is a single oral dose of NVP given to an HIV-infected woman in labor and another dose given to the baby within three days of birth. This regimen was found to be effective, easy to administer and affordable in resource-limited settings. The 2003 results of another study, NVAZ, demonstrated that when the mother was not able to receive the oral intrapartum single dose NVP, giving the baby the single dose of NVP at birth with the addition of one week of daily ZDV is more effective than giving the infant a single dose of NVP alone. There is no standard regimen for reducing the risk of HIV transmission through breastfeeding.

11. What are the implications of the PEPI Malawi study results?

The PEPI study demonstrated that both extended regimens, extended NVP alone and extended NVP+ZDV, significantly reduced HIV transmission through breastfeeding at 14 weeks of age. While there was no additional protection from the extended treatments after discontinuation at 14 weeks, the earlier benefits were maintained through at least 9 months of age. There does not appear to be an advantage of using two drugs, NVP+ZDV, over using NVP alone. This infant-only extended antiretroviral regimen is practical and effective in reducing HIV transmission and improving HIV-free survival in settings where breastfeeding is common.

Standard practices for preventing mother-to-infant transmission of HIV, which are based on guidelines issued by the World Health Organization and made by individual ministries of health, may be re-evaluated in light of these findings because they suggest that breastfeeding infants of HIV-infected mothers may benefit from extended infant antiretroviral drug administration.